Vito Marco Ranieri

Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock.

The role of drotrecogin alfa (activated) (DAA) in severe sepsis remains controversial and clinicians are unsure whether or not to treat their patients with DAA. In response to a request from the European Medicines Agency, Eli Lilly will sponsor a new placebo-controlled trial and history suggests the results will be subject to great scrutiny. An academic steering committee will oversee the conduct of the study and will write the study manuscripts. The steering committee intends that the study will be conducted with the maximum possible transparency; this includes publication of the study protocol and a memorandum of understanding which delineates the role of the sponsor. The trial has the potential to provide clinicians with valuable data but patients will only benefit if clinicians have confidence in the conduct, analysis and reporting of the trial. This special article describes the process by which the trial was developed, major decisions regarding trial design, and plans for independent analysis, interpretation and reporting of the data.

Anatomical and functional intrapulmonary shunt in acute respiratory distress syndrome

Objectives:The lung-protective strategy employs positive end-expiratory pressure to keep open otherwise collapsed lung regions (anatomical recruitment). Improvement in venous admixture with positive end-expiratory pressure indicates functional recruitment to better gas exchange, which is not necessarily related to anatomical recruitment, because of possible global/regional perfusion modifications. Therefore, we aimed to assess the value of venous admixture (functional shunt) in estimating the fraction of nonaerated lung tissue (anatomical shunt compartment) and to describe their relationship. Design:Retrospective analysis of a previously published study. Setting:Intensive care units of four university hospitals. Patients:Fifty-nine patients with acute lung injury/acute respiratory distress syndrome. Interventions:Positive end-expiratory pressure trial at 5 and 15 cm H2O positive end-expiratory pressures. Measurements and Main Results:Anatomical shunt compartment (whole-lung computed tomography scan) and functional shunt (blood gas analysis) were assessed at 5 and 15 cm H2O positive end-expiratory pressures. Apparent perfusion ratio (perfusion per gram of nonaerated tissue/perfusion per gram of total lung tissue) was defined as the ratio of functional shunt to anatomical shunt compartment. Functional shunt was poorly correlated to the anatomical shunt compartment (r2 = .174). The apparent perfusion ratio at 5 cm H2O positive end-expiratory pressure was widely distributed and averaged 1.25 ± 0.80. The apparent perfusion ratios at 5 and 15 cm H2O positive end-expiratory pressures were highly correlated, with a slope close to identity (y = 1.10·x −0.03, r2 = .759), suggesting unchanged blood flow distribution toward the nonaerated lung tissue, when increasing positive end-expiratory pressure. Conclusions:Functional shunt poorly estimates the anatomical shunt compartment, due to the large variability in apparent perfusion ratio. Changes in anatomical shunt compartment with increasing positive end-expiratory pressure, in each individual patient, may be estimated from changes in functional shunt, only if the anatomical-functional shunt relationship at 5 cm H2O positive end-expiratory pressure is known.

The influence of gender on the epidemiology of and outcome from severe sepsis

IntroductionThe impact of gender on outcome in critically ill patients is unclear. Weinvestigated the influence of gender on the epidemiology of severe sepsis andassociated morbidity and mortality in a large cohort of ICU patients in the regionof Piedmont in Italy.MethodsThis was a post-hoc analysis of data from a prospective, multicenter,observational study in which all patients admitted to one of 24 participatingmedical and/or surgical ICUs between 3 April 2006 and 29 September 2006 wereincluded.ResultsOf the 3,902 patients included in the study, 63.5% were male. Female patients weresignificantly older than male patients (66 ± 16 years vs. 63 ± 16 years,P < 0.001). Female patients were less likely to have severe sepsisand septic shock on admission to the ICU and to develop these syndromes during theICU stay. ICU mortality was similar in men and women in the whole cohort (20.1%vs. 19.8%, P = 0.834), but in patients with severe sepsis wassignificantly greater in women than in men (63.5% vs. 46.4%, P = 0.007).In multivariate logistic regression analysis with ICU outcome as the dependentvariable, female gender was independently associated with a higher risk of ICUdeath in patients with severe sepsis (odds ratio = 2.33, 95% confidence interval =1.23 to 4.39, P = 0.009) but not in the whole cohort (odds ratio = 1.07,95% confidence interval = 0.87 to 1.34).ConclusionIn this large regional Italian cohort of ICU patients, there were more male thanfemale admissions. The prevalence of severe sepsis was lower in women than in men,but female gender was independently associated with a higher risk of death in theICU for patients with severe sepsis.

Role and potentials of low-flow CO2 removal system in mechanical ventilation.

Purpose of reviewAn analysis of the technological implementation of extracorporeal CO2 removal (ECCO2R) techniques and of its clinical application. A new classification of ECCO2R, based on technological aspects, clinical properties and physiological performance, is proposed. Recent findingsThe use of a ventilation with lower tidal volumes has been proved successful in acute respiratory distress syndrome (ARDS) patients but can be extremely problematic, especially when dealing with respiratory acidosis. The implementation of ECCO2R devices can represent the missing link between the prevention of ventilator-induced lung injury and pH control. ECCO2R has attracted increasing interest because of new less-invasive approaches allowing an easier management of ARDS patients. Recent studies have also shown that ECCO2R can also be used in patients with exacerbation of chronic obstructive pulmonary disease (COPD) and as a bridge to lung transplantation. SummaryThe future ventilatory management of patients with acute respiratory failure may include a minimally invasive extracorporeal carbon dioxide removal circuit associated with the least amount of ventilatory support (noninvasive in COPD and/or invasive in ARDS) to minimize sedation, prevent ventilator-induced acute lung injury and nosocomial infections. Randomized clinical trials in the pipeline will confirm this fascinating hypothesis.

Long-Term Quality of Life Among Survivors of Severe Sepsis: Analyses of Two International Trials

Objectives:To describe the quality of life among sepsis survivors. Design:Secondary analyses of two international, randomized clinical trials (A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis [derivation cohort] and PROWESS-SHOCK [validation cohort]). Setting:ICUs in North and South America, Europe, Africa, Asia, and Australia. Patients:Adults with severe sepsis. We analyzed only patients who were functional and living at home without help before sepsis hospitalization (n = 1,143 and 987 from A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis and PROWESS-SHOCK, respectively). Interventions:None. Measurements and Main Results:In A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis and PROWESS-SHOCK, the average age of patients living at home independently was 63 and 61 years; 400 (34.9%) and 298 (30.2%) died by 6 months. In A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis, 580 patients had a quality of life measured using EQ-5D at 6 months. Of these, 41.6% could not live independently (22.7% were home but required help, 5.1% were in nursing home or rehabilitation facilities, and 5.3% were in acute care hospitals). Poor quality of life at 6 months, as evidenced by problems in mobility, usual activities, and self-care domains were reported in 37.4%, 43.7%, and 20.5%, respectively, and the high incidence of poor quality of life was also seen in patients in PROWESS-SHOCK. Over 45% of patients with mobility and self-care problems at 6 months in A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis died or reported persistent problems at 1 year. Conclusions:Among individuals enrolled in a clinical trial who lived independently prior to severe sepsis, one third had died and of those who survived, a further one third had not returned to independent living by 6 months. Both mortality and quality of life should be considered when designing new interventions and considering endpoints for sepsis trials.

Incidence and severity of primary graft dysfunction after lung transplantation using rejected grafts reconditioned with ex vivo lung perfusion

OBJECTIVES Ex vivo lung perfusion (EVLP) is a novel technique used to evaluate and recondition marginal or rejected grafts. Primary graft dysfunction (PGD) is a major early complication after lung transplantation (LTx). The use of marginal or initially rejected grafts may increase its incidence and severity. The aim of this study is to evaluate the incidence of PGD after LTx using rejected grafts reconditioned with EVLP. METHODS PGD has been evaluated immediately after LTx (t0) and after 72 h (t72) in patients receiving standard (Group A) or reconditioned (Group B) grafts. EVLP was performed using a controlled acellular perfusion according to the Toronto technique. RESULTS From July 2011 to February 2013, 36 LTxs have been performed: 28 patients (21 M/7 F, mean age 51.7 ± 14.7 years) in Group A and 8 (6 M/2 F, mean age 46.6 ± 9.8 years) in Group B (successful recondition rate of 73%, 8 of 11 cases). Incidence rate of PGD 3 at t0 and at t72 (Group A versus Group B) was 50 vs 37% (P = NS) and 25 vs 0% (P = NS), respectively. Post-transplant extracorporeal membrane oxygenation was required in 5 and 2 patients in Groups A and B, respectively (P = NS). CONCLUSIONS The use of initially rejected grafts treated with EVLP does not increase the incidence and severity of PGD after LTx. Although comparison of PGD 3 incidence in the two groups did not reach a statistical difference, all EVLP patients suffering from severe PGD early after transplant recovered normal lung function at 72 h, suggesting a protective role of EVLP against PGD occurrence and severity.

Extracorporeal membrane oxygenation in adult patients with acute respiratory distress syndrome.

Purpose of reviewTo examine the role of extracorporeal membrane oxygenation (ECMO) as potential therapeutic option for severe cases of acute respiratory distress syndrome (ARDS). Recent findingsThe use of ECMO to treat acute respiratory failure dramatically increased. Factors that may explain this increase in the use of ECMO are H1N1 pandemic influenza, results of recent clinical trials and not lastly the technological development and consequently the commercial pressure of the industry. Under these circumstances, clinicians urgently need clinical trials and formal indication, contraindication and rules for implementation to provide reproducible results. SummaryGuidelines from the Extracorporeal Life Support Organization still indicate ECMO for acute severe pulmonary failure potentially reversible and unresponsive to conventional management. The new definition of ARDS (Berlin definition) addresses clinicians to the best treatment options in respect of the severity of illness and allocates ECMO as a potential therapeutic option for patients with severe ARDS and a P/F ratio lower than 100 and proposed that the indication of ECMO may be shifted from the treatment of choice for refractory hypoxemia to the treatment of choice to minimize ventilator-induced lung injury.

Endotoxin Removal: How Far from the Evidence? The EUPHAS 2 Project

Since 1994, a polystyrene fiber cartridge used for extracorporeal hemoperfusion, to which polymyxin B is bound and immobilized, has been used in septic patients in order to absorb and remove circulating lipopolysaccharide, thereby neutralizing the effects of this endotoxin. This therapy gradually gained acceptance as the amount of evidence increased from initial small clinical studies to a carefully conducted systematic review, and ultimately to the multicentered randomized clinical trial conducted in Italy, entitled the EUPHAS Study (Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock). While the conclusions of this initial randomized controlled trial were in agreement with previous studies, it possessed some important limitations, including a slow accrual rate, enrolling only 64 patients between 2004 and 2007, inability to blind treating physicians, and a premature study termination based on the results of the scheduled interim analysis. These limitations resulted in a modest patient sample size, which may have overestimated the true magnitude of the clinical effect. Apart from Japan, Italy is the current primary user of polymyxin B-hemoperfusion in the treatment of sepsis, with about 600 cartridges being used per year. However, no structured collection of data has been attempted, resulting in the an opportunity to understand the effects of polymyxin B-hemoperfusion on a large, diverse sample size. In response, Italian investigators and users of this treatment have designed a new prospective multicentered, collaborative data collection study, entitled EUPHAS 2. The aim of the EUPHAS 2 project is to collect a large database regarding polymyxin B-hemoperfusion treatments in order to better evaluate the efficacy and biological significance of endotoxin removal in clinical practice. Additionally, this study aims to verify the reproducibility of the data currently available in the literature, evaluate the patient population chosen for treatment and identify subpopulations of patients who may benefit from this treatment more than others.

Lung transplantation: is it still an experimental procedure?

Purpose of review The number of lung transplants performed worldwide is low and early and late results are worse in comparison with other solid organ transplants. The present review will focus on these two aspects analyzing the causes and describing the possible strategies to overcome these limitations. Recent findings The use of grafts from marginal and from nonheart-beating donors may increase the number of lung transplantation (LTx) with good results. Implementation of donor protocol and optimization of donor management have been reported to be effective in increasing the pool of suitable grafts. Ex-vivo reconditioning technique may be also helpful to better evaluate and recondition usually rejected lungs. This may allow a significant increase in the number of lung transplants performed worldwide. Early and late results of LTx are mainly affected by primary graft dysfunction and the onset of obliterative bronchiolitis. Different strategies have been adopted to reduce the incidence of these two complications with controversial results. Summary LTx maintains some features of experimental procedure especially in terms of number of performed procedures and early and late results. The various strategies to overcome the limited number of available grafts appear effective but not universally applied and accepted. The different treatments of PDG and obliterative bronchiolitis are still disappointing. To date, the onset of PDG and obliterative bronchiolitis after LTx still significantly impacts on outcomes. A better understanding of the underlying mechanisms in the pathogenesis of primary graft dysfunction and obliterative bronchiolitis may provide improved therapeutic strategies.

Novel approaches to minimize ventilator-induced lung injury

Purpose of reviewTo discuss the mechanisms of ventilator-induced lung injury and the pro and cons of the different approaches proposed by literature to minimize its impact in patients with acute respiratory distress syndrome. Recent findingsMechanical ventilation is indispensable to manage respiratory failure. The evolution of knowledge of the physiological principles and of the clinical implementation of mechanical ventilation is characterized by the shift of interest from its capability to restore ‘normal gas exchange’ to its capability of causing further lung damage and multisystem organ failure. SummaryIf one of the essential teachings to young intensivists in the 1980s was to ensure mechanical ventilation restored being able to immediately drain a pneumothorax (barotrauma), nowadays priority we teach to young intensivists is to implement ‘protective’ ventilation to protect the lungs from the pulmonary and systemic effects of ventilator-induced lung injury (biotrauma). At the same time, priority of clinical research shifted from the search of optimal ventilator settings (best positive end-expiratory pressure) and to the evaluation of ‘super-protective’ ventilation that integrating partial or total extracorporeal support tries to minimize the use of mechanical ventilation.